What are the causes of renal parenchymal scarring (renal fibrosis)?

Causes of Renal Parenchymal Scarring (Renal Fibrosis)

Renal parenchymal scarring results from multiple distinct pathogenic mechanisms that damage different kidney compartments, ultimately leading to irreversible fibrosis through excessive extracellular matrix deposition and nephron loss.

Primary Mechanisms by Compartment

Glomerular Injury Leading to Focal Scarring

Chronic glomerular damage is the predominant cause of focal interstitial fibrosis with tubular atrophy (IF/TA), which represents true nephron loss and replacement scarring. 1

• Glomerulosclerosis from any cause triggers atrophy of the corresponding tubule, degeneration of that specific nephron, and subsequent focal interstitial fibrosis 2
• This focal pattern correlates directly with development of end-stage kidney disease and represents irreversible nephron loss 1
• Common glomerular causes include ANCA-associated glomerulonephritis, lupus nephritis, IgA nephropathy, and diabetic nephropathy 2, 1

Tubulointerstitial Injury Causing Diffuse Fibrosis

Primary injury to the tubulointerstitial compartment produces diffuse fibrosis independent of tubular atrophy, driven predominantly by interstitial inflammation. 1

• Urinary tract obstruction leads to diffuse fibrosis as the predominant chronic lesion pattern 1
• Interstitial inflammation independent of glomerular damage drives this diffuse scarring pattern 1
• This diffuse pattern does not correlate with long-term progression to end-stage kidney disease 1

Direct Tubular Injury

Primary tubular epithelial cell injury with consecutive tubular atrophy produces focal IF/TA even without chronic glomerular damage. 1

• Acute tubular necrosis from ischemia, toxins, or drugs triggers tubular atrophy and focal scarring 2, 1
• Folic acid nephropathy demonstrates this mechanism experimentally 1

Specific Disease Etiologies

Infectious Causes

Pyelonephritis drives renal scarring through excessive host inflammatory response rather than direct bacterial damage. 3

• Bacterial infection recruits neutrophils and inflammatory macrophages proportional to bacterial burden 3
• The extent of fibrosis correlates most significantly with inflammation severity at 7 and 28 days post-infection 3
• Renal mucosal injury, tubulointerstitial nephritis, and cortical fibrosis develop as sequelae 3
• 15% of children develop renal scarring after their first urinary tract infection 4, 5

Vascular and Ischemic Injury

Vascular endothelial cell dysfunction leads to luminal encroachment, altered vascular reactivity, and ischemic nephron loss. 2

• Nephrectomy causes reduction in renal mass followed by hyperfiltration injury in remaining glomeruli 2
• Renal artery occlusion or stenosis produces broad macroscopic scars from complete parenchymal destruction 1
• Ischemia-reperfusion injury triggers molecular signatures associated with subsequent fibrosis 3

Metabolic and Systemic Diseases

Fabry disease causes progressive renal scarring through lysosomal GL-3 accumulation triggering cellular dysfunction, inflammation, and ultimately glomerulosclerosis and interstitial fibrosis. 2

• Kidney outcome relates more directly to interstitial and glomerular fibrosis than to GL-3 deposits themselves 2
• Diabetic nephropathy progresses at rates comparable to Fabry disease 2
• Hypertension and diabetes are predominant risk factors for chronic kidney disease and subsequent fibrosis 2

Malignancy-Related Scarring

Renal cell carcinoma causes parenchymal scarring through malignant infiltration, paraneoplastic syndromes, and urinary tract obstruction. 2

• Renal fibrosis and tubular atrophy in chronic kidney disease increase risk of renal cell carcinoma development 2
• Uremia-related chronic inflammation and oxidative stress contribute to both cancer risk and fibrosis 2

Cellular and Molecular Mechanisms

The Myofibroblast as Central Effector

Activation of resident mesenchymal cells into myofibroblasts drives excessive collagen deposition regardless of initial injury type. 6, 7, 8

• Myofibroblasts produce excessive extracellular matrix, primarily collagen 6, 7
• This process is independent of disease etiology but depends on the fibrotic niche microenvironment 6
• Focal and diffuse fibrosis patterns show distinct collagen signatures and matrix compositions 1

Inflammatory Cascade

Tissue responses including inflammation triggered by lysosomal and cellular dysfunction lead to irreversible damage. 2

• Immune cell chemotaxis and leukocyte activation drive fibrogenesis 3
• Chronic inflammation in the interstitium specifically associates with diffuse fibrosis 1

Critical Clinical Distinctions

Focal vs. Diffuse Patterns

• Focal IF/TA represents true nephron loss from glomerular injury and predicts progression to end-stage kidney disease 1
• Diffuse fibrosis results from primary interstitial inflammation without nephron loss and does not predict renal failure 1
• Both patterns commonly coexist in ANCA-associated glomerulonephritis, lupus nephritis, and IgA nephropathy 1

Reversibility Considerations

• Broad macroscopic scars from infarction represent irreversible wound healing responses 1
• Some diffuse fibrosis may be reversible with treatment of underlying inflammation 7, 8
• Epigenetic changes (DNA methylation, RNA interference, chromatin remodeling) offer potential therapeutic targets 6

Common Pitfalls

• Do not assume all fibrosis is equivalent: Focal IF/TA with nephron loss has vastly different prognostic implications than diffuse interstitial fibrosis 1
• Do not overlook inflammation as the driver: In pyelonephritis, excessive host inflammation—not bacterial damage—causes scarring 3
• Do not ignore compartment-specific injury patterns: Glomerular, tubular, and interstitial injuries produce distinct fibrotic patterns requiring different therapeutic approaches 1